As discussed in WO03/03347, WO04/110459 and WO99/46279 androgen-dependent diseases, i.e. diseases whose onset or progress is aided by androgenic activity, are well known. These diseases include, but are not limited to, prostate cancer, other androgen-dependent neoplasms such as prostatic intraepithelial neoplasia, benign prostatic hyperplasia, acne, seborrhea, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia and polycystic ovarian syndrome. Estrogen-dependent diseases, i.e. diseases whose onset or progress is aided by estrogenic activity, are also well known. These include but are not limited to breast cancer, endometriosis, leiomyoma and precocious puberty. Androgenic and estrogenic activity may be suppressed by administering androgen receptor antagonists or estrogen receptor antagonists respectively, see for example WO 94/26767 and WO 96/26201. Androgenic and estrogenic activity may also be reduced by suppressing ovarian or testicular secretions by known methods, see for example WO 90/10462, WO 91/00731, WO 91/00733, and WO86/01105. Examples of such anti-androgenic agents include LHRH agonists (e.g. leuprolide and zoladex) and LHRH antagonists (e.g. abarelix and cetrorelix).
Androgenic and estrogenic activity may also be reduced by suppressing androgen or estrogen biosynthesis using inhibitors of enzymes that catalyze one or more steps of such biosynthesis. These include inhibitors of 5alpha-reductase Type 1 and/or Type 2 (for example. finasteride, SKF105,657, LY191,704, LY320,236, dutasteride, Flutamide, nicalutamide, bicalutamide); inhibitors of 17alpha-hydroxylase/C17-20 lyase (for example YM116, CB7630 and liarozole); and inhibitors of 17beta-HSD Types 3 and 5. Inhibitors of 17beta-hydroxysteroid dehydrogenase Type 5 are described in WO 97/11162. Novel inhibitors of both Type 3 and Type 5 17beta-hydroxysteroid dehydrogenase are described in WO 99/46279.
Mammalian 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) are NAD(H) or NADP(H)-dependent enzymes which catalyse, besides other reactions, the final steps in male and female sex hormone biosynthesis. These enzymes convert inactive 17-ketosteroids into their active 17beta-hydroxy forms or catalyze the oxidation of the 17beta-hydroxysteroids into the inactive 17beta-keto forms. Because both estrogens and androgens have the highest affinity for their receptors in the 17beta-hydroxy form, 17beta-HSD enzymes play an essential role in the tissue-selective regulation of the activity of sex steroid hormones.
At present, 11 human members of the 17beta-HSD enzyme family have been described (Types 1-5, 7, 8, and 10-14). The human 17beta-HSD family members share less than 30% similarity in their primary structure. The 17beta-HSDs are expressed in distinct, though in some cases, overlapping patterns. The different types of 17beta-HSDs also differ in their substrate and cofactor specificities. In intact cells in culture, the 17beta-HSDs catalyze the reaction in a unidirectional way: e.g. Types 1, 3, 5 and 7 use NADP (H) as a cofactor and catalyze the reductive reaction (activation), while Types 2, 4, and 8 catalyze the oxidative reaction (inactivation) using NAD (H) as a cofactor (see e.g. Labrie et al. (2000) Trends Endocrinol Metab., 11, 421-7).
Due to their essential role in the tissue-selective regulation of the activity of sex steroid hormones, 17beta-HSDs can be involved in the occurrence and development of both estrogen-sensitive pathologies (e.g. breast, ovarian, uterine and endometrium cancers) and androgen-sensitive pathologies (e.g. prostate cancer, benign prostatic hyperplasia, acne, hirsutism). Furthermore, many types of 17beta-HSD have been shown to be involved in the pathogenesis of particular human disorders. For example, 17beta-HSD3 is known to be involved in the development of pseudohermaphroditism, 17beta-HSD8 plays a role in polycystic kidney disease, and 17beta-HSD4 is implicated in bifunctional enzyme deficiency. Therefore treatment of sex steroid-sensitive disease by administration of specific inhibitors of the 17beta-HSD enzymes has been suggested, optionally in combination with potent and specific anti-estrogens and anti-androgens (Labrie F et al. (1997) Steroids, 62, 148-58).
As each type of 17beta-HSD has a selective substrate affinity, directional (reductive or oxidative) activity in intact cells, and a particular tissue distribution, selectivity of drug action should be achieved by targeting a particular 17beta-HSD enzyme. By individual modulation of the particular 17beta-HSDs it is possible to influence or even control the local and paracrine concentration of estrogens and androgens in different target tissues.
The 17beta-HSD Type 3 enzyme (17beta-HSD3) is a well-characterized member of the 17beta-HSD family. Most of the 17beta-HSDs are expressed in a wide variety of tissues, however the 17beta-HSD3 enzyme is found to be expressed almost exclusively in the testis. 17beta-HSD3 has a crucial role in androgen biosynthesis. It converts 4-androstene-3,17-one (A) to testosterone (T). The physiological significance of 17beta-HSD3 is undeniable. Mutations in the 17beta-HSD3 gene have been found to lead to decreased testosterone formation in the foetal testis, and consequently to a human inter-sex disorder termed male pseudohermaphroditism (Geissler, W. M. et al. (1994) Nat. Genet. 7, 34-9).
Prostate tumours remain androgen-responsive for some time; the presence of active androgens regulates the proliferation and differentiation of the tumour cells. At present, androgen deprivation is the only effective systemic hormonal therapy available for prostate cancer. The development of selective inhibitors of 17beta-HSD3 is a therapeutic approach for the treatment of androgen-dependent disease (Labrie et al. (2000) Trends Endocrinol. Metab. 11, 421-7). Furthermore, Oefelein et al. reported that a GnRH analogue fails, in nearly 20% of cases, to achieve castrated levels of testosterone in men (Oefelein, M. G. & Cornum, R. (2000) J. Urol. 164, 726-9). In order to improve the response rate to endocrine therapy for men with prostate cancer it may be important to selectively inhibit testicular 17beta-HSD3 activity. Besides prostate cancer, many other androgen-sensitive diseases, i.e. diseases whose onset or progress is aided by androgenic activity, may be treated by selectively inhibiting 17beta-HSD3 activity. These diseases include, but are not limited to, benign prostatic hyperplasia, prostatitis, acne, seborrhea, hirsutism, androgenic alopecia, precocious puberty (usually associated with an excess of androgen secretion, often of adrenal origin), adrenal hyperplasia, and polycystic ovarian syndrome (associated with an excess of androgen secretion by the ovaries). Furthermore, considering the fact that 17beta-HSD3 is found mainly in the testis, the development of potent inhibitors could be of interest for blocking spermatogenesis as an anti-fertility agent for males.
Current therapies for the treatment of androgenic and estrogenic-dependent diseases include the use of glucocorticoids to block adrenal secretions, and luteinizing hormone releasing hormone (LHRH) agonists to cause medical castration. Both therapies are associated with undesirable side effects. An improved therapy would include compounds that specifically inhibit Type 3 17beta-hydroxysteroid dehydrogenase, while avoiding inhibition of other 17beta-hydroxysteroid dehydrogenases.
Several reversible or irreversible inhibitors of the 17beta-HSD3 enzymes of steroidal and even non-steroidal origin are already known in the literature. The characteristics of these inhibitory molecules are reviewed in Poirier, D. (2003) Curr. Med. Chem. 10, 453-77. For example, U.S. Pat. No. 6,541,463 discloses androsterone-derived inhibitors for 17beta-HSD3. These derivatives have been synthesised by parallel solid and liquid-phase chemistry, and some of these compounds showed 2 to 18-fold higher inhibitory activity than that of the natural substrate of the enzyme, A-dione, used itself as a inhibitor. Furthermore, WO01/42181 discloses benzyl-tetralins, the chemical structure of which is related to that of the phytoestrogen biochanin, as 17beta-HSD3 inhibitors. Furthermore, WO 98/32724, WO 98/30556 and WO99/12540 disclose tetralone, benzopyrane and benzofuranone derivatives, which have 17beta-HSD inhibitory activity, for the treatment of hormone-sensitive diseases.
There is a need for the development of compounds that selectively inhibit the 17beta-HSD3 enzyme, while desirably failing to substantially inhibit other members of the 17beta-HSD protein family, or other catalysts of sex steroid degradation or activation. In particular, it is an aim of the present invention to develop selective inhibitors of the 17beta-HSD3 enzyme, whereby in addition the compounds have no or only pure antagonistic binding affinities to the androgen receptor.
Aspects of the invention are defined in the appended claims.